title: A mechanistic pharmacodynamic model of IRAK-4 drug inhibition in the Toll-like receptor pathway.
abstract: The TLR pathway has been implicated in the pathogenesis of numerous diseases. IRAK-4 is integral to this pathway, making it a viable target for therapeutic intervention. This paper describes the application of a mechanistic pharmacodynamic model to assess the impact of IRAK-4 inhibition on the TLR-4 pathway. The model uses a minimal number of rate equations, molecular species, and parameters to characterize TLR signal transduction biology, including ligand-receptor interaction, protein complex formation, protein phosphorylation, negative regulation, and cytokine production. The model successfully reproduces the dynamic responses of TNFα to LPS stimulation, the tolerance to sequential LPS bolus dosing, the burst following a LPS bolus or infusion, and the modulation of pathway biomarkers following administration of an IRAK-4 inhibitor. Drug dosing schemes are evaluated for simulated disease states. The results emphasize the significance of LPS kinetics on response dynamics and the utility of a mechanistic model to help translate drug efficacy.
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, MA, 02140, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Nolan
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Bree
authors.forename: Anup
authors.initials: A
authors.lastname: Zutshi
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases